Nitroso halides

ABSTRACT

A pharmaceutical formulation of a compound of formula (II&#39;&#39;)   wherein Y is a lower alkyl group, in association with a pharmaceutically acceptable carrier, as an antibacterial product, and methods involving the preparation and reductive cyclization of a compound of formula (IV)   wherein X is a lower alkyl group or a hydroxymethyl group.

United States Patent [191 Wood et a1.

[ Nov. 4, 1975 NITROSO HALIDES [75] Inventors: Hamish Christopher SwanWood,

Glasgow, Scotland; Alexander Stuart, Bromley; Adrian Charles WardCurran, Harrow, both of England; Saieba Al-Hassan, Baghdad, Iraq [73]Assignee: Burroughs Wellcome Co., Research Triangle Park, NC.

221 Filed: Feb. 19, 1974 21 App1.No.:443,504

Related US. Application Data [62] Division of Ser. No. 162,297, July 13,1971, Pat. No.

[30] Foreign Application Priority Data July 27, 1970 United Kingdom36289/70 [52] US. Cl. 260/488 F; 260/633 [51] Int. Cl. C07C 81/04; C07C81/08 [58] Field of Search 260/488 F, 633, 647

[56] References Cited UNITED STATES PATENTS 12/1966 Defer et a1 260/647X 9/1968 Roscn et al. 260/647 X OTHER PUBLICATIONS Thorne, ChemicalSociety Journal, 4271-4275.

Primary ExaminerRichard L. Raymond Attorney, Agent, or Firm-Donald Brown[57] ABSTRACT A pharmaceutical formulation of a compound of for mula(II') Y k I on, HZN H 3 wherein Y is a lower alkyl group, in associationwith a pharmaceutically acceptable carrier, as an antibacterial product,and methods involving the preparation and reductive cyclization of acompound of formula wherein X is a lower alkyl group or a hydroxymethylgroup.

6 Claims, No Drawings NITROSO HALIDES specification of British Pat.Application No. 03301/70.

HM cH,oH

N XCH, 1 H CH It has now been found that the compounds represented bythe following formula (II') or their tautomers or pharmaceuticallyacceptable salts thereof,

wherein Y is a lower alkyl group, preferably one which contains amethylenic group (CH attached to the ring system, are also useful asbacteriostats or in antibacterial products. For instance they producesubstantial inhibition of the dihydrofolate synthesis upon whichbacteria, such as E. coli, are dependent for their growth, indicatinggeneral antagonism of bacterial metabolic processes.

As used herein and throughout the specification, the term lower alkylgroup" refers to a straight or branched chain alkyl group having 1 to 4carbon atoms.

The compound wherein Y is a methyl group is especially preferred.

A compound of formula (II), or its salt, may also be used in in vitropharmacological investigations in clinical and diagnostic testsestablishing, for instance, the properties of bacteria. When used as abacteriostat, it is present in a concentration of 1 to 180 mg of bas/ml.of the solution in which the organism grows in the absence of thecompound. A further use of a compound (II), when in solution, is in thetreatment of wounds,

for example after surgery, to prevent the growth of bac- CH NOHceutically acceptable acid or alkali, such as hydrochloric acid,sulphuric acid, tartaric acid, maleic acid, ammonia, sodium hydroxideand tetramethyl ammonium hydroxide.

According to one aspect of the present invention there are providedpharmaceutical formulations comprising the compound (II) or tautomericforms thereof, or pharmaceutically acceptable salts thereof, inassociation with a pharmaceutically acceptable carrier.

The substance may be presented advantageously in discrete units, such astablets, capsules, cachets or ampoules, each containing a predeterminedamount of the compound. It may also be presented as a powder orgranules, as a solution or suspension in an aqueous or non-aqueous(optionally emulsified) liquid, or as an ointment. For parenteral use,the formulations must be sterile and are presented in sealed containers.The formulations of this invention may be made by any of the methods ofpharmacy, and may include one or more of the following accessoryingredients: diluents, solutes, buffers, flavouring, binding,dispersing, surface-active, thickening, lubricating and coatingmaterials, preservatives, antioxidants, and ointment bases, and anyother acceptable excipients.

The above-mentioned lowest member of the group of compounds (H'), the6-methyl-substituted compound, has been prepared according to the methoddescribed by Pfleiderer and Zondler (Chem. Ber. 1966, 99, 3008), inwhich 3-amino-3-methylbutan-2-one hydriodide is reacted with2-amino-4-chloro-6-hydroxy-5- nitropyrimidine and the productreductively cyclised. However the preparation of the amino ketone iscumbersome, involving the formation of an undesirable and potentiallyexplosive azide intermediate derivative. The amino ketone preparation istherefore expensive, and the final stages of the entire-process areunsatisfactory in many respects, in particular the amino ketoneundergoes self condensation and a number of side products are produced,with concomitant low yield of the desired pteridine.

A much improved method of synthesis of the compounds of formula (II),

N Z H CH, N (ll) mu H CH wherein Z is a lower alkyl group, preferablyone which contains a methylenic group attached to the ring system, or ahydroxymethyl group, has now been discovered which uses the intermediateof formula (IV) or, going one stage further back, that of formula (V).The compounds (II) can therefore be prepared according to the followingreaction sequence:

N0 N HN I z /k CH3 CH3 H N N NH- COZ HgN N CH (III) The compounds offormula (IV) are all novel and those of formula (V) are novel, exceptwhen Z is a methyl group, and these therefore form further aspects ofthe present invention.

The conversion of compound (IV) to compound (II) is carried out mostadvantageously in practice by effecting reductive cyclisation of theformer. This may be achieved by the use of reducing agents which arecapable of reducing the nitro group without attacking other parts of themolecule; for example it may be achieved readily by means of catalytichydrogenation using catalysts such as palladium charcoal, platinum, orRaney nickel, but reduction with sodium dithionite is especiallypreferred. This latter reagent is cheap, effects a rapid reaction anddoes not require a source of hydrogen as do the catalytic reagents. Thereductive cyclisation may be carried out under a variety of conditions,the pH of the medium required depending on the choice of reducingagents. An alkaline medium is preferred for reduction with sodiumdithionite and also for hydrogenation using Raney nickel.

Another manner of carrying out the above reductive cyclisation toprepare compound (II) proceeds through the isolation of the ketonicintermediate of formula (III), which may be purified by methods known inthe art, e.g. by recrystallisation, by reaction of compound (IV) with anacid, preferably a moderately strong acid. The acid may be, for example,an organic acid such as trifluoroacetic or benzenesulphonic or a mineralacid, especially a dilute mineral acid, such as hydrochloric orsulphuric acid. The compound (III) is then reductively cyclised tocompound (II) as hereinbefore described for compound (IV), the reactionmost probably passing through the diamino pyrimidine intermediate.

Preparation of the novel pyrimidine ketoxime (IV) is readily effected byreacting the compound of formula (V) or a salt thereof withreadly-available 2-amino4- halogeno-6-hydroxy-S-nitro pyrimidine. Thehalogeno substituent is a bromine, iodine or fluorine atom or mostpreferably a chlorine atom, and an acid addition salt of the compound(V) may conveniently be a hydrohalide, preferably the hydrochloride. Thereaction is desirably effected in the presence of an acid binding agentsuch as a weak base, for example sodium carbonate, sodium acetate, or inparticular a tertiary amine, such as triethylamine.

The compound (V) or a salt thereof can be prepared by reacitng a nitrosohalide, for practical purposes most preferably the chloride, of formula(VI) with ammonia solution. Conveniently ammonia gas is bubbled throughthe reaction solvent, which may be an alkanol such as methanol, therebypreventing any precipitation during the process. The compound (VI) canin turn be prepared by an addition reaction with the appropriatenitrosyl halide, e.g. nitrosyl chloride. The reagent may be availablecommercially or could conveniently be prepared in situ, for instance,from a nitrosating agent with a concentrated hydrohalic acid. Suitablenitrosating agents include isoamyl nitrite and methyl nitrite.

In formulae (VII) and (VI), the definition of X is the same as thatdefined herein for Z, except that X may be an ester group, such as anacyl ester CH O.CO.R, where R is a lower alkyl group. The sequence (VII)to (V) is especially applicable when X is a hydroxymethyl group.

The intermediates of formula (VI) are novel compounds, except when X isa methyl group, and form yet a further aspect of the present invention.

There are many ways of preparing compound (VII) wherein X is ahydroxymethyl group or an ester thereof, but it has been foundadvantageous and convenient to proceed:

a. when X is hydroxymethyl (VII') either i. by reduction of thecorresponding acid (IX) with a powerful reducing agent, especially anorgano metallic hydride, such as lithium aluminiumhydride, or preferablysodium dihydro-bis-2- methoxyethoxy aluminate; or

ii. by structural rearrangement of 3-methyl-3- hydroxybut-l-ene of theformula (VIII) to the thermodynamically more stable alcohol of formula(VII), for example by means of boric acid;

b. when X is an acyl ester group, such as--CI-I O.-

COR.

either i by reaction of the alcohol of formula (VII') with theappropriate acid anhydride; or

ii. from 3-methyl-3-hydroxybut-lene (VIII) by structural rearrangement,as described under (a) (ii), in the presence of the apropriate organicacid to give Compound (VI Ch\ CH CH /C=CHCO2H C=CH-CH,oH C CH=CH, CH CH,CH 0H (IX) (vu') (Vlll) C=CH CH,oCoR

(VII") Compound (VII") may then be converted with a nitrosating agent,as hereinbefore idefined, to the nitrosohalide of formula (VI), whichmay be further reacted to give the compound of formula (V) of a saltthereof, where Z is a hydroxymethyl group.The sequence (VIII) to (VII")to (VI) is especially preferred to the initial stages of the synthesis.

The compound of formula (V)'or a salt thereof may also be prepared fromthe corresponding ketone of formula (X) or a salt thereof, wherein Y isa lower alkyl group, preferably one which contains a methylenic groupattached to the ring system, by reaction with hydroxylamine or an acidsalt thereof. Advantageously at least one equivalent of sodium acetate,sodium carbonate or triethylamine is present to act as an acid bindingagent.

. CH, CH3

Compound (X) may itself be prepared, for example, according to thefollowing reaction scheme:

CH H

CH3 CH OH (xv) (XIV) crgn cu, H

wherein R is an alkyl, aryl or aralkyl group.

Nitropropane, which is readily available, is condensed with theappropriate aldehyde of formula (XV) in the presence of a strong basiccatalyst such as an alkali metal hydroxide or alkoxide. The product(XIV) is reduced, for example by catalytic hydrogenation, preferablyusing Raney nickel, to compound (XIII), the amino group is protected togive compound (XII), the hydroxyl group is oxidised, for example usingchromium trioxide in pyridine, to produce compound (XI), and finally theprotecting group is removed by hydrolysis, conveniently using a mineralacid. The protection of the amino group is readily achieved using-anacyl group, such as a benzoyl, acetyl or carbobenzoxy group, preferablythe benzoyl group.

According to the present invention in further aspects there are alsoprovided: a

l. The methods described herein for preparing any of the compounds offormula (II), comprising effect- 6 ing reductive cyclisation ofcompounds of formula (IV). i 2. The methods described herein forpreparing any of the compounds (IV) from (V), (V) from (VI) or (VII),(V) from (X) and (X) from (XIII). 3. Compounds 'of'formula (II), (IV),(V), (VI) and (X), whenever'prepared by am ethod as defined under (I),(2) or(3), respectively. 4.'As novel compounds of value as chemicalintermediates: g Compounds of formula (XI), as hereinbefore defined,especially 3-N-benzoylamino-3-methylbutan-2-one. The following Examplesillustrate the invention but are in no way intended to limit the scopeof the invention. Temperatures are in degrees Celsius.

EXAMPLE 1 Synthesis of Compounds of Formula (V) l. 3,3-dimethyl ally]alcohol (VII') (X=CH OH) a. A solution of 3,3-dimethylacrylic acid (20g.,

0.2M) in sodium-dried ether (200 ml.) was treated.

dropwise with 64 g. (0.2MI+lO%) of a,7 0% solution of sodium dihydro-bis(2-methoxyethoxy) aluminate in benzene, the temperature being maintainedat 0 until the addition was complete (about 1 hour). The reactionmixture was stirred for 5 hours at room temperature, and water was thenadded slowly. The sodium aluminate which precipitated was filtered off,and the filtrate was extracted with ether (4 X ml.) The combinedextracts were dried, the solvent was removed, and the residual oil wasdistilled to give 3,3-dimethylallyl alcohol as a colourless liquid b.p.5455/25 mm Hg. or

b. A mixture of 3-methyl-3-hydroxybut-l-ene (64 g.) and boric acid (60g.) was stirred at l 10C in an apparatus equipped for distillation. Thesubstituted butene distilled of gradually over 5 hours and was replacedwith a fresh supply at intervals throughout the 5 hours. The cooledreaction mixture was dilutedwith water, neutralised with solid sodiumcarbonate and extracted with ether. The ethereal extracts were brinewashed, dried and evaporated and theresidual oil distilled (13 g.)50-60/14 mm Hg.

2. 3,3-dirnethyl allyl acetate .(VII) (X=CII O.- CO.CH

a. 3,3-Dimethylallyl alcohol (4.3 g., 0.05 M) and acetic anhydride (6.5g., 0.07 M) were heated on a steam bath for 1 hour and them distilledfrom the same flask at water pump pressure. Thetotal distillate waspoured onto ice-water and the pH adjusted to 7.0 with sodium hydrixde,under ether. The ethereal layer was removed and the aqueous solutionextracted with ether (2 X 20 ml. The combined extracts were washed withbrine, dried and the solvent removed to give a pale yellow oil.Fractional distillation gave the 3,3-dimethylallyl acetate as acolourless oil (3.5 g.) b.p. 4043/20 mm Hg.

b. A. mixture of 3-methyl-3-hydroxybut-l-ene (32 g.), acetic acid (150ml.) and boric acid (30g) was stirred at for 4 hours. The cooledreaction mixture was diluted with water, neutralised with solid sodiumcarbonate and extracted with ether (3 X 50 ml.) The combined etherealextracts were brine washed, dried and the solvent removed giving a paleyellow oil (30 g,)

Distillation gave 3,3-dimethylallyl acetate as a colourless oil (22 g.)b.p. 44-45/14 mm Hg.

3. 3-chloro-3-methyl-2-nitrosobutan-1-ol (X=CH OH) 3,3-Dimethylallylalcohol (50 m1), iso-amyl nitrite (70 ml.) and glacial acetic acid (100ml.) were cooled in an ice-salt bath and treated with ice-coldconcentrated hydrochloric acid (40 ml) added dropwise with stirring.Glacial acetic acid (40 ml) was added slowly maintaining the temperatureat -5. Towards the end of the addition a white solid precipitated. Thereaction mixture was then stirred at 0 for a further 30 minutes andcooled in an acetone/CO bath for 15 minutes. The product was filteredthrough a large precooled Buchner funnel and washed with a little coldbenzene and dried. Recrystallisation from dioxan gave the desirednitrosobutanol as colourless needles (19 g.) m.p. 1 19.

4. 3-chlor0-3-methyl-2-nitroso-l-butyl acetate (Vl) (X=CH O.CO.CH

3,3-Dimethylallyl acetate (25 ml.), iso-amyl nitrite (45 ml.) andglacial acetic acid (65 ml.) were cooled in an ice-salt mixture. Anice-cold mixture of'concentrated hydrochloric acid (20 ml.) and glacialacetic acid (20 ml.) was added gradually with stirring. The solutionbecame green and towards the end of the addition a white solidprecipitated. The solid was collected by filtration and dried (13 g.)Recrystallisation from CCl 40/60 petrol gave the title compound asoolourless needes (10 g.) m.p. ll7l 19.

5. 3-chloro-3-methyl-2-nitrosobutane (VI) (X=CH A mixture of2-methylbut-2-ene (70 g.) and iso-amyl nitrite (100 ml.) was stirred inan ice-salt bath for 30 minutes and then concentrated hydrochloric acid(100 ml.) was added dropwise with stirring at such a rate as to keep thetemperature below (-l hour) A blue solution was obtained, and acrystalline paste gradually formed. The reaction mixture was stirred fora further 30 minutes below 5C, followed by cooling in an aceton'e/CObath for fifteen minutes. The pale blue precipitate was filtered andwashed with ice-cold ethanol (50 ml.) The product was dried in a streamof air until all traces of blue colour had gone, leaving the titlecompound as colourless crystals (60g.) 75.

6. 3-amino-3-methyl-2-hydroxyiminobutan1-ol hydrochloride (salt of v(Z=CH2OH) a. 3-Chloro-3-methyl-2-hitrosobutan-1-ol (10 g.) was dissolvedin dry methanol (200 ml.) saturated with ammonia at 0. The mixture wasthen left overnight at room temperature and evaporated to dryness invacuo at room temperature. The residue was extracted with hot drybenzene (200 ml.) andthe benzenein'soluble component extracted furtherwith hot secondary butanol (220 ml.). The secondary butanol extract wasevaporated to small volume and the product precipitated by dropwiseaddition of ether. This was filtered and dried in vacuo (7.5g.)m.p.l72173.

b. 3-Chloro-3-methyl-2-nitroso-l-butyl acetate (5 g.) was treated with amethanolic ammonia solution ml) and the mixture stirred at roomtemperature in a sealed flask for 2 days. Removal of the volatilematerial gave an oily solid which was triturated with ethanol and thesoluble component retained. Removal of the ethanol gave a residual solidwhich was triturated with hot acetone giving a creamy white powder (4g.) m.p.

7. 3-amino-3-methylbutan-Z-one oxime hydrochloride (Salt of V) (Z=CHevaporated to dryness in vacuo at room temperature and the residueextracted with hot dry benzene (900 ml.) followed by boiling secondarybutanol I 300 ml.).

The secondary butanol extract was evaporated in vacuo at roomtemperature to a thick slurry. This was cooled, filtered and dried invacuo (56 g.) m.p.

190 (decomp).

EXAMPLE 2 :Alternative (Synthesis of Compounds of Formula (V) I.3-nitro-3-methylbutan-2-ol (XlV) (Y=CH Freshly distilled acetaldehyde(27.3 g., 0.62 M was added portionwise to a well stirred solution of2-nitropropane (52.08 g. 0.62 M) in ethanol (30 ml.) and ION sodiumhydroxide (1.2 ml.), maintaining the reaction temperature at 3035. Aftertwo-thirds of the aldehyde had been added, a further 1.2 ml. of IONsodium hydroxide and 8 ml. of water was added followed by the remainingacetaldehyde, and the mixture stirred at room temperature for 4 days.Excess acetaldehyde and 2-nitropropane were. removed at the water pump.The residue was dissolvedin water (l00ml.) and extracted with ether (3 X50ml.). The combined ethereal extracts were brine washed, dried anddistilled to give the title compound as a colourless oil (26g) b.p.8293/14 mm Hg.

2. 3-amino-3-methylbutan 2-ol (XIII) (Y=CI-l 3-Nitro-3-methylbutan-2-ol(5g.,0.035 M) was dissolved in methanol (300 ml.) and hydrogenated overfreshly prepared Raney nickel (-2g) at room temperature and 4atmospheres pressure for 5 hours until there was no further visibleuptake of hydrogen. The nickel catalyst was removed by filtration andthe solvent evaporated to give the title compound as a colourless oil(3.6g).

3. 3-N-benzoylamino-3-methylbutan-2-ol 3) 3-Amino-3-methylbutan-2-ol(6.1 g.) was dissolved in benzene (120 ml.), treated with anhydroussodium carbonate (16 g.) and cooled to 10. The mixture was then treatedwith benzoylchloride (9.2 g.) in benzene (30 ml.) at 10 and left tostand at this temperature for 3 hours. After a further 2 hours at roomtemperature the reaction mixture was refluxed for 30 minutes, filteredhot and the solid extracted with hot benzene (2 X ml.) The combinedfiltrates were evaporated to 100 ml. and cooled. The colourlesscrystalline solid was collected and recrystallised from benzene ascolourless needles (5 g.) m.p. ll8120 4. 3-N-benzoylamino3-methylbutan-2-one 3) 3-N-Benzoylamino-3-methylbutan-2-ol (2.02g., 0.1M) in anhydrous pyridine (4 ml.) was added to the oxidising reagent,prepared by adding chromium trioxide (3 g., 0.03 M) to a vigorouslystirred, cooled solution of pyridine (35 ml.) over 15 minutes. Themixture was stirred at 0 for 30 minutes and then at room temperature for22 hours. The reaction mixture was poured 'on'to water (100 ml.) andextracted with ether (3 X 50 ml.) The combined extracts were washed withbrine, driedand 'e vaporated to give a white powder, whichrecrystallisedfrom benzene-petrol as colourless needles (Xll) 5.3-amino3-methylbutan-2 -one-hydrochloride (Salt of X) (Y=CH;,)

3N-Benzoylamino-3-methylbutan2-one l g.) was suspended in 20%hydrochloric acid 10 ml.), refluxed for 8 hours, cooled and theprecipitated benzoic acid filtered. The filtrate was evaporated and theresidue treated with water (2 ml.) and filtered to remove a furtherquantity of benzoic acid. The resultant filtrate was evaporated and theresidue triturated with cold ethanol (3 X 5 ml.) filtering, evaporatingthe filtrate and discarding the solid each time. The resultant residuewas recrystallised from ethanol-ether as colourless needles (500 mg.)mp. 212214.

This was then reacted with hydroxylamine in the presence oftriethylamine to give 3-amino3-methylbutan-2-one oxime hydrochloride(Salt of V) (Y=CH EXAMPLE 3 Synthesis of Compounds of Formula (11) l.2-amino 4-chloro-6-hydroxy-5-nitropyrimidine2-Amino-4-chloro-6-hydroxypyrimidine (7.5 g.) was dried over P 05, at0.5 mmHg for 2 hours, partially dis solved in concentrated sulphuricacid (9 ml.) and the slurry cooled to C and treated portionwise withfuming nitric acid (8 ml.) with constant stirring. The yellow solutionwas stirred for an additional 30 minutes at room temperature and thenpoured onto ice (30 g.). The pale yellow solid was filtered, washed withicewater and then ether and dried over P 0 at 0.5 mmHg giving the titlecompound as a pale yellow solid (8.32 g.) m.p. 260 (decomp.)

2. 2-amino-4-( 1 ,l -dimethyl-3'-hydroxyacetonyl-)amino-6-hydroxy-5-nitro pyrimidine oxime (IV) (Z=CH OH) 3-Amino-3-methyl-3-hydroxyiminobutan-1-ol hydrochloride (2.5 g.0 was dissolved inethanol (16 ml.) and treated with 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine (2.8 g) an triethylamine (2.8 g.), and the mixture stirred atroom temperature for 2 hours, at reflux for 4 hours and at roomtemperature for a further 8 hours. The reaction mixture was heated,filtered hot and the solid washed with hot ethanol. The ethanol wasremoved from the combined filtrates giving a pale yellow powder whichwas triturated with small amounts of ethanol. The powder wasrecrystallised from boiling water to give the title compound as anoiT-white power (1.5 g).

3. 2-amino-4-( l ,l -dimethylacetonyl)amino-6- hydroXy-Snitro-pyrimidineoxime (lV) (Z=CH 3-Amino-3-methylbutan-2-one oxime hyrochloride (5 g.),2-amino-4-chloro-6-hydroxy-S nitro pyrimidine (6 g.) and triethylamine l0 ml.) were refluxed in ethanol (200 ml.) for 16 hours. The reactionmixture was cooled and the white precipitate was collected and purifiedby dissolving in ZNammonium hydroxide solu' tion. Reprecipitation withglacial acetic acid gave the pyrimidinylamino-kctone oxime as a whitesolid (6.0 g.) m.p. 260 (decomp).

4. 2-amino-4-( 1 ,l -dimethyl-3 '-hydroxyacctonyl-)amino-6-hydroxy-5-nitro pyrimidine (lll) (Z=CH OH) 2-Amino-4-( l ,l'-dimethyl-3'-hydroxyacetonyl- )amino-o-hydroxyd-nitro pyrimidine oxime(2 g.) was dissolved in 2Nhydrochloric acid (200 ml.) and the so lutionheated on a steam bath for 2 hours. The reaction mixture wasconcentrated by rotary evaporation at 0.5

mm Hg. at 40 and the resultant solid triturated with acetone, filteredand dried. The yellow powder was recrystallised from boiling water as anoff-white powder (1 g)- 5. 2-amino4-( 1 ,l -dimethylacetonyl )amino-6-hydroxy-5-nitro pyrimidine (lll) (Z=CH 2-Amino4-( l ,l'-dimethylacetonyl)amino-6- hydroxy-5-nitropyrimidine oxime (6.0 g.) washydrolysed by refluxing for 10 minutes with 2N-hydrochloric acid. Thereaction mixture was cooled, filtered and neutralised with 0.880ammonium hydroxide to precipitate the pyrimidinylamino-ketone as acolourless crystalline solid (5.0 g.) m.p 289.

6. 2-amino-4-hydroxy-6-hydroxymethyl-7,7-dimethyl-7,8-dihydropteridine(ll) (Z=Ch OH) 2-Amino-4-( l ,l dimethyl-3'hydroxyacetonyl-)amino-6-hydroxy-5-nitropyrimidine (4 g.) was suspended in water (50 ml.heated on the steambath, and treated with solid sodium dithionite untilthe original solid had dissolved. After 5-10 minutes the solution wascooled, whereupon the off-white product began to separate out. This wascompleted by the addition of 0.880 ammonia to pH 8.5-9.0 (2.1 g) m.p.300.

In another experiment the pyrimidinylamino ketone was dissolvedinitially in 0.1'N sodium hydroxide followed by portionwise addition ofsodium dithionite and isolation of the product 1.6 g.).

7. 2-amino-4-hydroxy-7-8-dihydro-6,7,7-trimethylpteridine (ll) (X=CH2-Amino-4-( 1 ,l '-dimethylacetonylamino )-6 hydroxy-S-nitropyrimidine(2 g.) was dissolved in dilute ammonium-hydroxide, the solution warmedgently and soldium dithionite added portionwise until a colourlesssolution was obtained. The pH was adjusted to 7 with acetic acid and thedihydropteridine which precipitated was filtered and washed with water,ethanol and ether (1.75 g.) m.p. 298300.

8. 2-amino-4-hydroxy-6-hydroxymcthyl-7,7-dimethyl-7,8-dihydropteridine(ll) (Z=CH OH) Direct Method 2-Amino-4-( 1 ,l'-dimethyl-3'-hydroxyacetonyl) amino-6-hydroxy-5-nitro pyrimidine oxime(50 mg.) was dissolved in 0.1N sodium hydroxide (3 ml.) with warming ona steam bath. The warm solution was treated portionwise with sodiumdithionite until the yellow colour was discharged On cooling a whitesolid precipitated which was washed with water and dried giving thetitle compound as a pale yellow powder (40 mg.)

9. 2-amino-4-hydroxy-7,8-dihydro-6,7,7-trimethyl pteridine (ll) (Z=CHDirect Method 2-Amino-4( 1 ,l '-dimethylacetonylamino)'6-hydroxy-S-nitropyrimidine oxime (50 mg.) was dissolved in 0.1N sodiumhydroxide (3 ml.) with warming on the steam bath. The warm solution wastreated with sodium dithionite until the yellow colour was dis charged.This was collected, washed with water and dried to give the titlecompound as a pale yellow powder (35 mg).

(:1) Ingredients 2-Amino-4-hydroxy-7.8-dihydro- 6,7,7-trimethylpleridine(ll') Microcrystalline cellulose 500 mg mg The pteridine (ll'),.micirocrystalline cellulose and starch were granulated with a solutionof the methylhydroxyethylcellulose'in 50% aqueous ethyl alcohol. Themagnesium stearate was added to the dried granules, and the whole thencompressed.

EXAMPLE Ointment containing a compound (II') (a) Ingredients2-Amino-4-hydroxy-7,8-dihydro 2 g. 6,7.7-trimethylpteridine (ll) Whitesoft parafi'in 100 g.

b. Procedure The pteridine (II) was incorporatedin part of the whitesoft paraffin which had been softened by heat.

12 The rest of the white soft paraffin was added, and the wholethroughly mixed.

What we claim is: l. A compound of formula Hal C CH N0 wherein X is CHO.CO.R Hal is a halogen atom and R is lower alkyl.

2. A compound CH NO in which X is hydroxymethyl and Hal is a halogenatom.

3. A compound according to claim 1 in which Hal is a chlorine atom.

4. A compound according to claim 2 in which Hal is a chlorine atom.

5. A compound of claim 1 in which R is methyl.

'6. A compound of claim 3 in which R is methyl.

1. A COMPOUND OF FORMULA
 2. A compound
 3. A compound according to claim1 in which Hal is a chlorine atom.
 4. A compound according to claim 2 inwhich Hal is a chlorine atom.
 5. A compound of claim 1 in which R ismethyl.
 6. A compound of claim 3 in which R is methyl.